Identification and structure–activity relationships of substituted pyridones as inhibitors of Pim-1 kinase

A novel series of highly potent substituted pyridone Pim-1 kinase inhibitors is described. Structural requirements for in vitro activity are outlined as well as a complex crystal structure with the most potent Pim-1 inhibitor reported (IC50 = 50 nM). A hydrogen bond matrix involving the Pim-1 inhibitor, two water molecules, and the catalytic core, together with a potential weak hydrogen bond between an aromatic hydrogen on the R1 phenyl ring and a main-chain carbonyl of Pim-1, accounts for the overall potency of this inhibitor.

Graphical abstractA novel class of pyridone-based inhibitors of Pim-1 kinase is reported. A complex crystal structure of Pim-1/compound 1 (IC50 of 1 = 50 nM) defined an inhibitory mechanism of action.Figure optionsDownload full-size imageDownload as PowerPoint slide